We studied 193 Enterobacteriaceae isolates presenting diminished susceptibility to oxyimino-cephalosporins recovered in a Portuguese hospital (2004–2008). CTX-M-3 producers, firstly detected in Portugal, were associated with a Klebsiella pneumoniae microepidemic clone. Production of CTX-M–type enzymes (CTX-M-1/-3/-9/-14/-15/-32), age ≥65 years, and nosocomial infection were risk factors for higher nonsusceptibility to oxyimino-β-lactams. CMY-2 and DHA-1 β-lactamases were only identified in 1% of isolates.